Discovery of a Potent, Selective, and Cell-Active SPIN1 Inhibitor
The methyl-lysine reader protein SPIN1 plays important roles in various human diseases. However, targeting methyl-lysine reader proteins has been challenging. Very few cellularly active SPIN1 inhibitors have been developed. We previously reported that our G9a/GLP inhibitor UNC0638 weakly inhibited SPIN1. Here, we present our comprehensive structure-activity relationship study that led to the discovery of compound 11, a dual SPIN1 and G9a/GLP inhibitor, and compound 18 (MS8535), a SPIN1 selective inhibitor. We solved the cocrystal structure of SPIN1 in complex with 11, confirming that 11 occupied one of the three Tudor domains. Importantly, 18 displayed high selectivity for SPIN1 over 38 epigenetic targets, including G9a/GLP, and concentration dependently disrupted the interactions of SPIN1 and H3 in cells. Furthermore, 18 was bioavailable in mice. We also developed 19 (MS8535N), which was inactive against SPIN1, as a negative control of 18. Collectively, these compounds are useful chemical tools to study biological functions of SPIN1.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:67 |
|---|---|
| Enthalten in: |
Journal of medicinal chemistry - 67(2024), 7 vom: 11. Apr., Seite 5837-5853 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Xiong, Yan [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
|---|
| Anmerkungen: |
Date Completed 12.04.2024 Date Revised 25.04.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1021/acs.jmedchem.4c00121 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM370231309 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM370231309 | ||
| 003 | DE-627 | ||
| 005 | 20240425233321.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240328s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1021/acs.jmedchem.4c00121 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1386.xml |
| 035 | |a (DE-627)NLM370231309 | ||
| 035 | |a (NLM)38533580 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Xiong, Yan |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Discovery of a Potent, Selective, and Cell-Active SPIN1 Inhibitor |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 12.04.2024 | ||
| 500 | |a Date Revised 25.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a The methyl-lysine reader protein SPIN1 plays important roles in various human diseases. However, targeting methyl-lysine reader proteins has been challenging. Very few cellularly active SPIN1 inhibitors have been developed. We previously reported that our G9a/GLP inhibitor UNC0638 weakly inhibited SPIN1. Here, we present our comprehensive structure-activity relationship study that led to the discovery of compound 11, a dual SPIN1 and G9a/GLP inhibitor, and compound 18 (MS8535), a SPIN1 selective inhibitor. We solved the cocrystal structure of SPIN1 in complex with 11, confirming that 11 occupied one of the three Tudor domains. Importantly, 18 displayed high selectivity for SPIN1 over 38 epigenetic targets, including G9a/GLP, and concentration dependently disrupted the interactions of SPIN1 and H3 in cells. Furthermore, 18 was bioavailable in mice. We also developed 19 (MS8535N), which was inactive against SPIN1, as a negative control of 18. Collectively, these compounds are useful chemical tools to study biological functions of SPIN1 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a methyl-lysine |2 NLM | |
| 650 | 7 | |a Lysine |2 NLM | |
| 650 | 7 | |a K3Z4F929H6 |2 NLM | |
| 700 | 1 | |a Greschik, Holger |e verfasserin |4 aut | |
| 700 | 1 | |a Johansson, Catrine |e verfasserin |4 aut | |
| 700 | 1 | |a Seifert, Ludwig |e verfasserin |4 aut | |
| 700 | 1 | |a Gamble, Vicki |e verfasserin |4 aut | |
| 700 | 1 | |a Park, Kwang-Su |e verfasserin |4 aut | |
| 700 | 1 | |a Fagan, Vincent |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Fengling |e verfasserin |4 aut | |
| 700 | 1 | |a Chau, Irene |e verfasserin |4 aut | |
| 700 | 1 | |a Vedadi, Masoud |e verfasserin |4 aut | |
| 700 | 1 | |a Arrowsmith, Cheryl H |e verfasserin |4 aut | |
| 700 | 1 | |a Brennan, Paul |e verfasserin |4 aut | |
| 700 | 1 | |a Fedorov, Oleg |e verfasserin |4 aut | |
| 700 | 1 | |a Jung, Manfred |e verfasserin |4 aut | |
| 700 | 1 | |a Farnie, Gillian |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Oppermann, Udo |e verfasserin |4 aut | |
| 700 | 1 | |a Schüle, Roland |e verfasserin |4 aut | |
| 700 | 1 | |a Jin, Jian |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of medicinal chemistry |d 1963 |g 67(2024), 7 vom: 11. Apr., Seite 5837-5853 |w (DE-627)NLM000006602 |x 1520-4804 |7 nnns |
| 773 | 1 | 8 | |g volume:67 |g year:2024 |g number:7 |g day:11 |g month:04 |g pages:5837-5853 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1021/acs.jmedchem.4c00121 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 67 |j 2024 |e 7 |b 11 |c 04 |h 5837-5853 | ||